Jonas Elizabeth A.

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Jonas
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Elizabeth A.
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  • Preprint
    Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase
    ( 2011-06) Alavian, Kambiz N. ; Li, Hongmei ; Collis, Leon P. ; Bonanni, Laura ; Zeng, Lu ; Sacchetti, Silvio ; Lazrove, Emma ; Nabili, Panah ; Flaherty, Benjamin ; Graham, Morven ; Chen, Yingbei ; Messerli, Shanta M. ; Mariggio, Maria A. ; Rahner, Christoph ; McNay, Ewan ; Shore, Gordon ; Smith, Peter J. S. ; Hardwick, J. Marie ; Jonas, Elizabeth A.
    Anti-apoptotic BCL-2 family proteins such as Bcl-xL protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-xL enhances the efficiency of energy metabolism. Our evidence suggests that Bcl-xL interacts directly with the beta subunit of the F1FO ATP synthase, decreasing an ion leak within the F1FO ATPase complex and thereby increasing net transport of H+ by F1FO during F1FO ATPase activity. By patch clamping submitochondrial vesicles enriched in F1FO ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-xL increases the membrane leak conductance. In addition, recombinant Bcl-xL protein directly increases ATPase activity of purified synthase complexes, while inhibition of endogenous Bcl-xL decreases F1FO enzymatic activity. Our findings suggest that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-xL expressing neurons.
  • Preprint
    Contributions of Bcl-xL to acute and long term changes in bioenergetics during neuronal plasticity
    ( 2013-10-28) Jonas, Elizabeth A.
    Mitochondria manufacture and release metabolites and manage calcium during neuronal activity and synaptic transmission, but whether long term alterations in mitochondrial function contribute to neuronal plasticity that underlies changes in organism behavior patterns is still poorly understood. Although normal neuronal plasticity may determine learning, in contrast a persistent decline in synaptic strength or neuronal excitability may portend neurite retraction and eventual somatic death. Anti-death proteins such as Bcl-xL provide neuroprotection at the neuronal soma during cell death stimuli, but also appear to enhance neurotransmitter release and synaptic growth and development. It is proposed that Bcl-xL performs these functions through its ability to regulate mitochondrial release of bioenergetic metabolites and calcium, its ability to rapidly alter mitochondrial positioning and morphology as well as its role in interacting with proteins that directly alter synaptic vesicle recycling. Bcl-xL translocates acutely to sub-cellular membranes during neuronal activity to achieve these changes. After stressful stimuli, pro-apoptotic cleaved delta N Bcl-xL (ΔN Bcl-xL)-induced mitochondrial ion channel activity leads to synaptic depression and this is regulated by caspase activation. During physiological states of decreased synaptic stimulation, loss of mitochondrial Bcl-xL and low level caspase activation occur prior to the onset of long term decline in synaptic efficacy. The degree to which Bcl-xL changes mitochondrial membrane permeability may control the direction of change in synaptic strength. The small molecule Bcl-xL inhibitor ABT-737 has been useful in defining the role of Bcl-xL in synaptic processes. Bcl-xL is crucial to the normal health of neurons and synapses and its malfunction may contribute to neurodegenerative disease.
  • Article
    Parkinson's disease protein DJ-1 regulates ATP synthase protein components to increase neuronal process outgrowth
    (Springer Nature, 2019-06-13) Chen, Rongmin ; Park, Han-A ; Mnatsakanyan, Nelli ; Niu, Yulong ; Licznerski, Pawel ; Wu, Jing ; Miranda, Paige ; Graham, Morven ; Tang, Jack ; Boon, Agnita J. W. ; Cossu, Giovanni ; Mandemakers, Wim ; Bonifati, Vincenzo ; Smith, Peter J. S. ; Alavian, Kambiz N. ; Jonas, Elizabeth A.
    Familial Parkinson’s disease (PD) protein DJ-1 mutations are linked to early onset PD. We have found that DJ-1 binds directly to the F1FO ATP synthase β subunit. DJ-1’s interaction with the β subunit decreased mitochondrial uncoupling and enhanced ATP production efficiency while in contrast mutations in DJ-1 or DJ-1 knockout increased mitochondrial uncoupling, and depolarized neuronal mitochondria. In mesencephalic DJ-1 KO cultures, there was a progressive loss of neuronal process extension. This was ameliorated by a pharmacological reagent, dexpramipexole, that binds to ATP synthase, closing a mitochondrial inner membrane leak and enhancing ATP synthase efficiency. ATP synthase c-subunit can form an uncoupling channel; we measured, therefore, ATP synthase F1 (β subunit) and c-subunit protein levels. We found that ATP synthase β subunit protein level in the DJ-1 KO neurons was approximately half that found in their wild-type counterparts, comprising a severe defect in ATP synthase stoichiometry and unmasking c-subunit. We suggest that DJ-1 enhances dopaminergic cell metabolism and growth by its regulation of ATP synthase protein components.
  • Article
    Exposure to hypoxia rapidly induces mitochondrial channel activity within a living synapse
    (American Society for Biochemistry and Molecular Biology, 2004-11-23) Jonas, Elizabeth A. ; Hickman, John A. ; Hardwick, J. Marie ; Kaczmarek, Leonard K.
    One of the earliest effects of hypoxia on neuronal function is to produce a run-down of synaptic transmission, and more prolonged hypoxia results in neuronal death. An increase in the permeability of the outer mitochondrial membrane, controlled by BCL-2 family proteins, occurs in response to stimuli that trigger cell death. By patch clamping mitochondrial membranes inside the presynaptic terminal of a squid giant synapse, we have now found that several minutes of hypoxia trigger the opening of large multiconductance channels. The channel activity is induced concurrently with the attenuation of synaptic responses that occurs under hypoxic conditions. Hypoxia-induced channels are inhibited by NADH, an agent that inhibits large conductance channels produced by a pro-apoptotic fragment of BCL-xL in these synaptic mitochondria. The appearance of hypoxia-induced channels was also prevented by the caspase/cysteine protease inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone (Z-VAD-fmk), which inhibits proteolysis of BCL-xL during hypoxia. Both NADH and Z-VAD-fmk reduced significantly the rate of decline of synaptic responses during hypoxia. Our results indicate that an increase in outer mitochondrial channel activity is a very early event in the response of neurons to hypoxia and suggest that this increase in activity may contribute to the decline in synaptic function during hypoxia.